Matise - Signalling Mechanisms Regulating Cell Communication Flashcards
Major receptor classes (4)
1) Ion channels
2) Steroid hormone receptors
3) Protein kinase receptors
4) 7 alpha helix receptors
Ligand-gated ion channels
Ligand binding opens/closes channel, allowing ion flow across membrane. Ton of diseases causing by improper activation/inactivation
- ex: cystic fibrosis caused by loss of functional chlorine channels, mucus buildup
- gain of function mutations = dominant (constant activation, inapropro)
Tetrodotoxin
Blocks sodium channels irreversibly, so fatal
Nuclear Steroid Hormone Receptors
Ex: estrogen. hormone binding receptor causes receptor to dissociate from a chaperone protein, then complex dimerizes with another receptor-hormone complex. Dimer enters nucleus, binds DNA promoter (response element) to cause gene activation. Overexpressed in cancers, treat with competitive receptor binders (tamoxifen)
Protein Kinase receptors
kinase: phosphorylates. Has extra, trans, intramembrane components. Usually found as dimer. Main subtypes: tyrosine kinases, serine/threonine kinases
- Activation of PKR brings subunits together to form dimer. Subunits phosphorylate each other, recruit cytosolic proteins
Phosphorylation
reversible by phosphotases. Can turn hydrophobic region–>hydrophilic, changing molecular conformations.
Grb (G-protein receptor binding) proteins
bind phosphorylated receptors, contain SH2 domain which recognizes phosphorylated tyrosine
SoS (GEF) - Son of Sevenless
Binds Grb, activates small G-proteins like Ras
Ras (Rat Sarcoma)
typical small G-protein, ~200 others. Activates transcription factors, through MAPK for example. Oncogenic when mutation prevents GTP hydrolysis, so permanently “on”.
GEFS (Guanine nucleotide exchange factors)
Activate G-proteins by exchanging GDP–>GTP (inactive–>active)
-ex: eIF1 requires GEF
GAPS - GTPase activating proteins
inactivate proteins by converting GTP–>GDP
PKR Signaling Pathway
PRK is activated, phosphorylates Grb. SoS binds Grb’s SH2 domain. SoS acts as GEF for ras, GDP–>GTP. Ras activates further cellular targets until it is inactivated by a GAP, GTP–>GDP
MAPK
mitogen activated protein kinase. Activates transcription factors following phosphorylation cascade caused by Ras, one of many activated by Ras.
Neurofibromatosis Type I
Mutation in gene for Ras GAP causes overactive Ras.
Noonan Syndrome
Mutation coding SHP2 causes overactive Ras
7 - Helix Receptors
Named for 7 alpha-helix structure, most abundant receptor. Coupled to 3-part G-proteins, A, B, G. Ligand binding causes A phosphorylation, separation of subunits, activation of stuff downstream
G-protein alpha subunit types (3)
1) Gs-alpha: phosphorylate PKA (activates adenyl cyclase)
2) Gi-alpha: hydrolyzes PKA (inactivates adenyl cyclase)
3) Gq-alpha: activates PLC, phospholipase C
7 alpha helix receptor desensitization (B-adrenergic receptor ex)
B-adrenergic receptor is activated by epinephrine. Receptor + ligand complex is substrate for BARK, B-adrenergic receptor kinase. Phosphorylation by BARK causes B-arrestin to bind. This prevents Gs from binding, preventing activity even with epinephrine present.
Gs-alpha /Gi-alpha calcium regulation
Gs activates adenyl cyclase–>cAMP–>PKA–>Ca2+ release. Gi deactivates adenyl cyclase, cutting off Ca2+ release.
Gq-alpha calcium regulation
Gq activates Phospholipase C (PLC) –> PiP2 –> DAG + IP3. IP3–>Ca2+ release, Ca2+ + IP3 activate PKC (protein kinase C)
Protein Kinase C (PKC) Activation
PKC has two binding domains required for kinase activation, self-blocked by its C1 and C2 domains when inactive. DAG binds one, Ca2+ allows the other to be bound by PS (phosphatidyl serine), activating PKC
Calmodulin
Binds calcium to become activated (4 subunits each bind). Activates CAMK, calmodulin-activated protein kinase.
CAMK Activation
Like PKC, CAMK is inactive when its subunit blocks active site. Ca2+ - bound calmodulin binds inhibitory domain of CAMK, making active site accessible.
-CAMK key to AD, musculoskeletal disorders, cancer
Agonists vs. Antagonists
Agonists: activate receptor pathways (activators)
Antagonists: inactivate receptor pathways (repressors)
